Autoimmune disorders are diseases caused by the body producing an inappropriate immune response against its' own tissues, in which the immune system creates T lymphocytes and autoantibodies that attack one's own cells, tissues, and/or organs. Researchers have identified 80-100 different autoimmune diseases and suspect at least 40 additional diseases have an autoimmune basis.
Autoimmune disorders are classified into two types, organ-specific (directed mainly at one organ) and non-organ-specific (widely spread throughout the body). Examples of organ-specific autoimmune disorders are insulin-dependent Type 1 diabetes, which affects the pancreas, Celiac disease, which affects the lining of the small intestine, Hashimoto's thyroiditis and Graves' disease, which affect the thyroid gland, pernicious anemia, which affects the stomach, Addison's disease, which affects the adrenal glands, chronic active hepatitis, which affects the liver, and myasthenia gravis, which affects the muscles. Examples of non-organ-specific autoimmune disorders are rheumatoid arthritis, multiple sclerosis, and lupus.
One of the most prevalent organ-specific autoimmune diseases, Type 1 diabetes, is characterized by the production of autoantibodies that target the insulin-secreting pancreatic beta cells. The disease pathogenesis involves T cell infiltration into the islets of the pancreas, which subsequently destroys insulin producing beta cells, and results in overt symptoms of disease. In most cases, T cells can respond to an antigen only when the antigen is properly presented by an antigen-presenting cell expressing the appropriate major histocompatibility complex (MHC) molecule. Thus, T cell immune response to an antigen requires recognition by the T cell receptor of an antigen coupled to a MHC molecule, and this recognition requires the assembly of a tri-molecular complex between an antigen, a MHC molecule, and a T cell receptor.
Evidence strongly indicates that insulin/proinsulin is a key or primary auto-antigen in the development of type 1 diabetes in the NOD (non-obese diabetic) mouse model. Initial cloning of T cells from islets of NOD mice led to the discovery that the native insulin B chain amino acids 9-23 (B: 9-23 insulin peptide) is the dominant antigenic peptide epitope presented by the class II MHC molecule I-A. Mice lacking the native B: 9-23 sequence fail to develop diabetes and development of insulin autoantibodies and insulitis are markedly decreased. Restoring the native B: 9-23 sequence with an islet transplant (but not bone marrow transplant) or peptide immunization, or a native proinsulin transgene, restores anti-insulin autoimmunity and generates CD4 T cells that cause diabetes.
The major genetic determinant of islet autoimmunity and diabetes in human and animal models are genes within the major histocompatibility complex, and in particular, class II MHC alleles. The NOD mouse's unique sequence of IA (homologous to human DQ) and lack of expression of I-E (shared with many standard mouse strains) are essential for the development of diabetes.
Celiac disease is an autoimmune disorder of the small intestine that affects between 1 in 100 and 1 in 300 people depending on the region of the world. The disease occurs in people of all ages and causes pain and discomfort in the digestive tract, chronic constipation and diarrhea, failure to thrive in children, anemia, and fatigue. The disease is caused by a reaction to gliadin, a prolamin (gluten protein) found in wheat, and other common grains such as barley and rye, in which the immune system cross-reacts with the small-bowel tissue, causing an inflammatory autoimmune reaction. The only known effective treatment is a lifelong gluten-free diet.
There exists a need in the art for safer and more effective methods for treating or slowing the progression or development of autoimmune disorders, such as autoimmune diabetes (type 1 diabetes, T1D) and Celiac disease (gluten sensitivity). This disclosure addresses these needs by providing molecules and formulations useful in the treatment and prevention of autoimmune diseases while achieving other advantages discussed more fully below.